**4.2 Blood glucose estimation**

Plasma glucose estimation has high intraindividual biological variability (4– 14%). This is accounted for by method of sample collection and storage, lifestyle measures while preparing for sample collection like exercise, calorie restriction and difficulty in ensuring fasting state. About 3-8 mg/dl/hr. of glucose is lose in a sample kept at room temperature. Therefore, in interpreting blood glucose test result, the

need to be conversant with causes of intraindividual and interindividual variation of blood glucose is necessary. Such variability can be grouped as

**4.3 Specimen for glucose estimation**

*DOI: http://dx.doi.org/10.5772/intechopen.96549*

Glucose can be measured in whole blood, serum, or plasma, but plasma is recommended for diagnosis. It can also be measured in capillary, venous or arterial blood. It is essential that in a repeat sampling for confirmation of blood glucose result, the same type of sampling used previously must be use. The molality of glucose (i.e., amount of glucose per unit water mass) in whole blood and plasma is identical. Although red blood cells are essentially freely permeable to glucose, the concentration of water (kg/L) in plasma is 11% higher than that of whole blood depending on the haematocrit, increasing to 15% at a haematocrit of 0.55 and decreasing to 8% at a haematocrit of 0.30 [39]. Therefore, glucose concentrations in plasma are 11% higher than whole blood if the hematocrit is normal. Glucose concentrations in heparinized plasma are reported to be 5% lower than in serum [40]*.* This may be caused by water shifting from red blood cells to plasma sequel to effect of anticoagulants. In feed (OGTT) state capillary glucose is higher by about [mean of 1.7 mmol/L (30 mg/dL), equivalent to 20–25%*]* than in venous blood*, but*

*Oral Glucose Tolerance Test (OGTT): Undeniably the First Choice Investigation…*

*the* mean difference in fasting samples is only 0.1 mmol/L (2 mg/dL) [41]*.*

**4.4 Fasting plasma glucose (FPG): a tool in screening for dysglycaemia**

there is associated progressively greater risk of developing micro- and

In 2003, the ADA reviewed its diagnostic criteria when it found out that the FPG

stated in the earlier classifications does not give corresponding hyperglycaemic impact compared to the OGTT results. The threshold for IFG was lowered from 6.1 mmol/L to 5.6 mmol/L [44] dependent on ROC curve analysis indicating that a cut-point of 5.4–5.5 mmol/L gives the best combination of sensitivity and specificity for predicting future diabetes, and this consequently increased the overall prevalence of IFG approximately three- to four-fold, though WHO and IDF maintained this as FPG 6.1–6.9 mmol/L. To date the searching to finding the corresponding FPG

Although both IGT and IFG are associated with resistance to insulin and increased insulin secretion, they do not identify identical patient populations and are not equivalent in predicting development of T2DM or cardiovascular events [45]. People with isolated IFG predominantly have hepatic insulin resistance and normal muscle insulin sensitivity, whereas individuals with isolated IGT have

macrovascular complications.

**119**

to what is normal or IGT is still ongoing.

In 1997, ADA Expert Committee on the Diagnosis and Classification of Diabetes Mellitus [42] recommended universal use of FPG for screening and diagnosis of diabetes mellitus because of its ease of administration, convenience, acceptability to patients, and lower cost in comparison to the OGTT and also based on assumption that the measurement reproducibility would be better. Since the goal and premise of diabetes management is the prevention of diabetes-associated complications, and this goal is best achieved when the disease is diagnosed at an early stage, the committee lowered the diagnostic threshold of FPG from 7.8 mmol/L to 7.0 mmol/L and also created a new category, defined as individuals exhibiting FPG levels between 6.1 and 6..9 mmol/L, called impaired fasting glucose (IFG) to describe the zone between the upper limit of normal FPG and the lower limit of the diabetic FPG. The IFG was believed at that time to be analogous to the zone between the upper limit of a normal 2-hr plasma glucose and the lower limit of the diabetic 2-hr plasma glucose described by IGT and was adapted by WHO in 1999 [43]**.** The FPG of 6.1 mmol/L was adopted by both ADA [44] and WHO [43] as the upper limit of "normoglycaemia" because this is the level above which first-phase of insulin secretion is lost in response to intravenous glucose and is also the level at which


On the basis of biological variation, glucose analysis having analytical imprecision 3.3%, bias 2.5%, and total error 7.9%, may produce classification errors, although imprecision is usually low at the diagnostic decision limits. It is also believed generally that glucose assay is highly reproducible across laboratories, however, a recent survey conducted in 6,000 US laboratories clearly documented a significant bias in glucose assessment in as many as 41% of them, yielding a misclassification of glucose tolerance in 12% of subjects [27]**.** The coefficients of variation of A1c, FPG, and 2-h PG were demonstrated to be 3.6%, 5.7%, and 16.6% respectively [28]**,** reflecting both biological and analytical variability.

Preanalytical processing of blood samples can markedly affect the results of plasma glucose readings because ongoing glycolysis by erythrocytes and leukocytes prior to centrifugation lowers its concentration [29, 30]. A study reported 5–7% [0.6 mmol/L (10 mg/dl)] an average rate of glycolysis per hour [31]**.** This varies with the glucose concentration, temperature*,* white blood cell count and other factors [32]*, for example,* it has been estimated that pre-analytical variability of FPG is 5–10% and the within day-day variability is 12–15%. Glycolysis can be attenuated by inhibition of enolase with sodium fluoride (2.5 mg fluoride/ml of blood) or, less commonly, lithium iodoacetate (0.5 mg/ml of blood). A citrate tubes should be use if a delay in centrifugation is expected because citrate more rapidly inhibits glycolysis [30]**.** It should be noted that although fluoride maintains long-term glucose stability, the rates of decline of glucose in the first hour after sample collection in tubes with and without fluoride are virtually identical [31]**.** Currently, both WHO and ADA recommend that for preanalytical processing for plasma glucose measurements involves venous blood collection into sodium fluoride (NaF) tubes with placement in ice-water slurry prior to centrifugation within 30 min of sample collection [33, 34]. The benefit of this policy is demonstrated in the following studies: An observed increase rate of GDM from 11.6% to 20.6% on changing to a protocol of centrifuging blood collected into NaF tubes within 10 min of venipuncture compared to delayed centrifugation was noted [35]**.** A study in Ireland showed a 2.7-fold higher (38.1% compared with 14.2%) when the ADA preanalytic protocol was followed compared with the previous standard practice of collecting blood into NaF tubes, leaving them at room temperature, and centrifuging after collection of all three samples [36]**.** Similarly, the impact of long delays in centrifugation for OGTT samples collected in NaF tubes on GDM diagnosis in Western Australia was estimated to be an under diagnosis rate of 62% [37]. In HAPO, a reference study for GDM, blood samples for all glucose measurements were collected into NaF tubes, placed in ice-water slurry immediately after phlebotomy, and kept that way until they could be centrifuge and separated [38].

*Oral Glucose Tolerance Test (OGTT): Undeniably the First Choice Investigation… DOI: http://dx.doi.org/10.5772/intechopen.96549*

### **4.3 Specimen for glucose estimation**

need to be conversant with causes of intraindividual and interindividual variation of

a. The biological variability is substantially greater than analytical variability

On the basis of biological variation, glucose analysis having analytical impreci-

sion 3.3%, bias 2.5%, and total error 7.9%, may produce classification errors, although imprecision is usually low at the diagnostic decision limits. It is also believed generally that glucose assay is highly reproducible across laboratories, however, a recent survey conducted in 6,000 US laboratories clearly documented a

significant bias in glucose assessment in as many as 41% of them, yielding a misclassification of glucose tolerance in 12% of subjects [27]**.** The coefficients of variation of A1c, FPG, and 2-h PG were demonstrated to be 3.6%, 5.7%, and 16.6%

Preanalytical processing of blood samples can markedly affect the results of plasma glucose readings because ongoing glycolysis by erythrocytes and leukocytes prior to centrifugation lowers its concentration [29, 30]. A study reported 5–7% [0.6 mmol/L (10 mg/dl)] an average rate of glycolysis per hour [31]**.** This varies with the glucose concentration, temperature*,* white blood cell count and other factors [32]*, for example,* it has been estimated that pre-analytical variability of FPG is 5–10% and the within day-day variability is 12–15%. Glycolysis can be attenuated by inhibition of enolase with sodium fluoride (2.5 mg fluoride/ml of blood) or, less commonly, lithium iodoacetate (0.5 mg/ml of blood). A citrate tubes should be use if a delay in centrifugation is expected because citrate more rapidly inhibits glycolysis [30]**.** It should be noted that although fluoride maintains long-term glucose stability, the rates of decline of glucose in the first hour after sample collection in tubes with and without fluoride are virtually identical [31]**.** Currently, both WHO and ADA recommend that for preanalytical processing for plasma glucose measurements involves venous blood collection into sodium fluoride (NaF) tubes with placement in ice-water slurry prior to centrifugation within 30 min of sample collection [33, 34]. The benefit of this policy is demonstrated in the following studies: An observed increase rate of GDM from 11.6% to 20.6% on changing to a protocol of centrifuging blood collected into NaF tubes within 10 min of venipuncture compared to delayed centrifugation was noted [35]**.** A study in Ireland showed a 2.7-fold higher (38.1% compared with 14.2%) when the ADA preanalytic protocol was followed compared with the previous standard practice of collecting blood into NaF tubes, leaving them at room temperature, and centrifuging after collection of all three samples [36]**.** Similarly, the impact of long delays in centrifugation for OGTT samples collected in NaF tubes on GDM diagnosis in Western Australia was estimated to be an under diagnosis rate of 62% [37]. In HAPO, a reference study for GDM, blood samples for all glucose measurements were collected into NaF tubes, placed in ice-water slurry immediately after phlebotomy, and kept that way until

respectively [28]**,** reflecting both biological and analytical variability.

they could be centrifuge and separated [38].

**118**

blood glucose is necessary. Such variability can be grouped as

*Type 2 Diabetes - From Pathophysiology to Cyber Systems*

b. Analytical imprecision <3.3%

c. Bias <2.5%

d. Total error < 7.9%

e. Glucose assay 4%

f. Biological CV 6.9%

Glucose can be measured in whole blood, serum, or plasma, but plasma is recommended for diagnosis. It can also be measured in capillary, venous or arterial blood. It is essential that in a repeat sampling for confirmation of blood glucose result, the same type of sampling used previously must be use. The molality of glucose (i.e., amount of glucose per unit water mass) in whole blood and plasma is identical. Although red blood cells are essentially freely permeable to glucose, the concentration of water (kg/L) in plasma is 11% higher than that of whole blood depending on the haematocrit, increasing to 15% at a haematocrit of 0.55 and decreasing to 8% at a haematocrit of 0.30 [39]. Therefore, glucose concentrations in plasma are 11% higher than whole blood if the hematocrit is normal. Glucose concentrations in heparinized plasma are reported to be 5% lower than in serum [40]*.* This may be caused by water shifting from red blood cells to plasma sequel to effect of anticoagulants. In feed (OGTT) state capillary glucose is higher by about [mean of 1.7 mmol/L (30 mg/dL), equivalent to 20–25%*]* than in venous blood*, but the* mean difference in fasting samples is only 0.1 mmol/L (2 mg/dL) [41]*.*

#### **4.4 Fasting plasma glucose (FPG): a tool in screening for dysglycaemia**

In 1997, ADA Expert Committee on the Diagnosis and Classification of Diabetes Mellitus [42] recommended universal use of FPG for screening and diagnosis of diabetes mellitus because of its ease of administration, convenience, acceptability to patients, and lower cost in comparison to the OGTT and also based on assumption that the measurement reproducibility would be better. Since the goal and premise of diabetes management is the prevention of diabetes-associated complications, and this goal is best achieved when the disease is diagnosed at an early stage, the committee lowered the diagnostic threshold of FPG from 7.8 mmol/L to 7.0 mmol/L and also created a new category, defined as individuals exhibiting FPG levels between 6.1 and 6..9 mmol/L, called impaired fasting glucose (IFG) to describe the zone between the upper limit of normal FPG and the lower limit of the diabetic FPG. The IFG was believed at that time to be analogous to the zone between the upper limit of a normal 2-hr plasma glucose and the lower limit of the diabetic 2-hr plasma glucose described by IGT and was adapted by WHO in 1999 [43]**.** The FPG of 6.1 mmol/L was adopted by both ADA [44] and WHO [43] as the upper limit of "normoglycaemia" because this is the level above which first-phase of insulin secretion is lost in response to intravenous glucose and is also the level at which there is associated progressively greater risk of developing micro- and macrovascular complications.

In 2003, the ADA reviewed its diagnostic criteria when it found out that the FPG stated in the earlier classifications does not give corresponding hyperglycaemic impact compared to the OGTT results. The threshold for IFG was lowered from 6.1 mmol/L to 5.6 mmol/L [44] dependent on ROC curve analysis indicating that a cut-point of 5.4–5.5 mmol/L gives the best combination of sensitivity and specificity for predicting future diabetes, and this consequently increased the overall prevalence of IFG approximately three- to four-fold, though WHO and IDF maintained this as FPG 6.1–6.9 mmol/L. To date the searching to finding the corresponding FPG to what is normal or IGT is still ongoing.

Although both IGT and IFG are associated with resistance to insulin and increased insulin secretion, they do not identify identical patient populations and are not equivalent in predicting development of T2DM or cardiovascular events [45]. People with isolated IFG predominantly have hepatic insulin resistance and normal muscle insulin sensitivity, whereas individuals with isolated IGT have

normal to slightly reduced hepatic insulin sensitivity and moderate to severe muscle insulin resistance [46]. Individuals with isolated IFG have reduction in both firstphase (0–10 min) during IVGT and early phase (first 30 min) during OGTT insulin secretion but maintained the late-phase (60–120 min) response during OGTT, while Isolated IGT apart from having defect in early-phase insulin secretion in response to OGTT also has a severe deficit in late-phase insulin secretion [47].

The change in the diagnostic procedure has brought a complex and variable effect on the prevalence of diabetes and on subjects diagnosed. Many studies have reported that FPG and 2-hr plasma glucose do not identify the same people as having diabetes. The difference between the prevalence of diabetes based on the FPG and 2-hr criteria varied from 4.0% to 13.2% in the 16 European survey in the DECODE study. In that study [56], of the 1517 people with newly diagnosed diabetes, 40% met only the FPG criterion, 31% met only the 2-hr criterion and 29% met both criteria. In the DECODA study [49], of 1215 subjects with diabetes by either criterion, only 449 (37%) met both criteria, of the 995 subjects with 2-hr ≥11.1 mmol/L, 546 (55%) had non-diabetes FPG value, and of the 669 subjects with FPG ≥7.0 mmol/L, 220 (33%) had nondiabetes 2-hr value. In the two studies the concordance rate ranges between 29–37%. In the NHANES study data cited in the 1997 ADA report showed 38% of subjects with newly diagnosed diabetes using only ADA criteria were missed when OGTT was carried out in the same population [42]. An even larger discrepancy was observed for the categories of IFG and IGT. In DECODA study, more than three quarter (≥3/4) of the subjects with IGT would be classified as normal if only the FPG criteria is used. Degree of hyperglycaemia, age, sex, BMI and ethnicity influence the concordance. The severer the hyperglycaemia the better the agreement between the two criteria. It might therefore be appropriate to use the FPG alone in subjects with clinical symptoms of diabetes to confirm. It is inappropriate to use it as the only test in the general population for epidemiological purposes, or in cohort with slightly higher glycaemia but without any symptoms because a large proportion of subjects diagnosed by 2-hr criteria would not be identified by the FPG particularly in Asians. In 1999, WHO recommended retaining the use of OGTT for epidemiological purposes, and this appears to be particularly important for the Asian population. The 2-hr criterion is more sensitive in the elderly and fasting criterion in the mid-aged. Barrett-Conner, et al. [57] reported that 70% of women and 48% of men aged 50–89 years had new diabetes diagnosed solely by elevated 2-hr plasma glucose. Similarly, in the Early Diabetes Intervention Program study [58], 24% and 50% of subjects with OGTTconfirmed diabetes had FPG levels between 5.5 and 6.0 and 6.1–6.9 mmol/L, respectively. Still in a further study, an isolated elevation of 2-hr glucose (2-hr glucose ≥11.1 mmol/L and FPG <7.0 mmol/L) identified as high as 65%(61/94) of those with newly diagnosed diabetes while 76%(644/845) who were normal by fasting blood glucose were identified with IGT and these individuals carry high risk of cardiovascular disease events [59]. A recent report showed that even if the concordance between the WHO and ADA criteria increased with this lower cutoff of IFG, 29% of patients with diabetes revealed by an OGTT and 57% with IGT would still have remained undiagnosed using FPG [59]**.** All individuals with IFG should have an OGTT, as a significant number (approximately 5%, but up to 20%, in some

*Oral Glucose Tolerance Test (OGTT): Undeniably the First Choice Investigation…*

*DOI: http://dx.doi.org/10.5772/intechopen.96549*

populations) will already have diabetes by 2-hr post challenge criteria [60]**,** so why

Impaired glucose tolerance (IGT), not diagnosed with FPG estimation, is associated with risk of cardiovascular events almost as high as in subjects with diabetes which is not similarly observed in people with IFG necessitating ADA to lowered the threshold for IFG from 6.1 mmol/L to 5.6 mmol/L in order to detect more subjects with pre-diabetes [61]. Consequently, with regards to the assessment of the risk of mortality and cardiovascular disease events, these discrepancies are crucially important. Therefore, in screening programs, clinical research, and populationbased epidemiological studies, where participants often lack diabetes symptoms or complications, an OGTT is commonly used to detect diabetes, thus adding to the diabetic "pool" an equal-sized group of subjects with unrecognized diabetes and it is

delaying diagnosis, why not start with OGTT in the first place.

misleading trying to assess glucose homeostasis without information on

post-prandial glucose metabolism.

**121**

The prevalences of IFG and IGT varies widely, varied considerably among different ethnic groups [48]**,** differ significantly in their age and sex distribution; and increase with advancing age. IGT is more frequent in women than in men [49]. A study of 1,245 Italian telephone company employees followed for 11.5 years found that, unlike baseline IGT, baseline IFG did not predict progression to DM, and the categories only overlapped 40% of the time [48]. The natural history of both IFG and IGT is variable, with approx 25% progressing to diabetes, 50% remaining in their abnormal glycaemic state, and 25% reverting to NGT over an observational period of 3-5 years [50, 51].

#### **4.5 Advantages of using FPG in screening for dysglycaemia**

American Diabetes Associated did not recommend OGTT to be used commonly in the diagnosis of type 1 and 2 diabetes because it was thought that if FPG is appropriately use it will identify almost the same number of dysglycaemia in the population as the OGTT, and that OGTT is not practicable in routine practice and in many studies OGTT is found to be poorly reproducible, with an estimated rate of only about 50–66% [52].

#### **4.6 Disadvantages of FPG in screening for dysglycaemia**

The fasting blood glucose testing in nondiabetic persons poorly identify early signs of dysglycaemia because high postprandial glucose marks the journey of first signs of abnormal glucose regulation and this best predict cardiovascular outcome. Fasting is not really the central issue and it seems to be overemphasized in diagnosing dysglycaemia.

One problem well known in the measurement of FPG in population studies is the difficulty in ensuring that all the participants have complied with the instructions about fasting [53]. Consequently, some participants with completely normal glucose homeostasis might have been misclassified into impaired fasting glucose category or, more rarely, even into a diabetes category. More so, FPG represents glucose handling during the moment of fasting period only (particularly so, of that moment of blood sampling), and this is affected easily by short-term lifestyle changes such as over activity, stress and drug ingestions. Therefore under these conditions subjects may be classified wrongly if only FPG is used. Knowledge of intraindividual variability of FPG concentrations is essential for meaningful interpretation of patient values. A study of healthy individuals [mean glucose, 4.9 mmol/L (88 mg/ dL)] exhibited within- and between-subject CVs of 4.8–6.1% and 7.5–7.8%, respectively [34]**.** Recent evidence revealed a diurnal variation in FPG, with mean FPG higher in the morning than in the afternoon, indicating that many cases of undiagnosed diabetes would have been missed in patients seen in the afternoon [54]**.** A study with repeated OGTT in 31 nondiabetic adults at 48-hr intervals, demonstrated FPG varied by 10% in 22 participants (77%) and by 20% in 30 participants (97%) [44]**.** Similarly, in population studies of subjects with newly diagnosed diabetes showed a wide distribution of FPG, ranging in one study from <5.0 mmol/1 to >30.0 mmol/L [55]. As a consequence, the sensitivity of the OGTT is naturally higher, given the current criteria.

*Oral Glucose Tolerance Test (OGTT): Undeniably the First Choice Investigation… DOI: http://dx.doi.org/10.5772/intechopen.96549*

The change in the diagnostic procedure has brought a complex and variable effect on the prevalence of diabetes and on subjects diagnosed. Many studies have reported that FPG and 2-hr plasma glucose do not identify the same people as having diabetes. The difference between the prevalence of diabetes based on the FPG and 2-hr criteria varied from 4.0% to 13.2% in the 16 European survey in the DECODE study. In that study [56], of the 1517 people with newly diagnosed diabetes, 40% met only the FPG criterion, 31% met only the 2-hr criterion and 29% met both criteria. In the DECODA study [49], of 1215 subjects with diabetes by either criterion, only 449 (37%) met both criteria, of the 995 subjects with 2-hr ≥11.1 mmol/L, 546 (55%) had non-diabetes FPG value, and of the 669 subjects with FPG ≥7.0 mmol/L, 220 (33%) had nondiabetes 2-hr value. In the two studies the concordance rate ranges between 29–37%. In the NHANES study data cited in the 1997 ADA report showed 38% of subjects with newly diagnosed diabetes using only ADA criteria were missed when OGTT was carried out in the same population [42]. An even larger discrepancy was observed for the categories of IFG and IGT. In DECODA study, more than three quarter (≥3/4) of the subjects with IGT would be classified as normal if only the FPG criteria is used. Degree of hyperglycaemia, age, sex, BMI and ethnicity influence the concordance. The severer the hyperglycaemia the better the agreement between the two criteria. It might therefore be appropriate to use the FPG alone in subjects with clinical symptoms of diabetes to confirm. It is inappropriate to use it as the only test in the general population for epidemiological purposes, or in cohort with slightly higher glycaemia but without any symptoms because a large proportion of subjects diagnosed by 2-hr criteria would not be identified by the FPG particularly in Asians. In 1999, WHO recommended retaining the use of OGTT for epidemiological purposes, and this appears to be particularly important for the Asian population. The 2-hr criterion is more sensitive in the elderly and fasting criterion in the mid-aged. Barrett-Conner, et al. [57] reported that 70% of women and 48% of men aged 50–89 years had new diabetes diagnosed solely by elevated 2-hr plasma glucose. Similarly, in the Early Diabetes Intervention Program study [58], 24% and 50% of subjects with OGTTconfirmed diabetes had FPG levels between 5.5 and 6.0 and 6.1–6.9 mmol/L, respectively. Still in a further study, an isolated elevation of 2-hr glucose (2-hr glucose ≥11.1 mmol/L and FPG <7.0 mmol/L) identified as high as 65%(61/94) of those with newly diagnosed diabetes while 76%(644/845) who were normal by fasting blood glucose were identified with IGT and these individuals carry high risk of cardiovascular disease events [59]. A recent report showed that even if the concordance between the WHO and ADA criteria increased with this lower cutoff of IFG, 29% of patients with diabetes revealed by an OGTT and 57% with IGT would still have remained undiagnosed using FPG [59]**.** All individuals with IFG should have an OGTT, as a significant number (approximately 5%, but up to 20%, in some populations) will already have diabetes by 2-hr post challenge criteria [60]**,** so why delaying diagnosis, why not start with OGTT in the first place.

Impaired glucose tolerance (IGT), not diagnosed with FPG estimation, is associated with risk of cardiovascular events almost as high as in subjects with diabetes which is not similarly observed in people with IFG necessitating ADA to lowered the threshold for IFG from 6.1 mmol/L to 5.6 mmol/L in order to detect more subjects with pre-diabetes [61]. Consequently, with regards to the assessment of the risk of mortality and cardiovascular disease events, these discrepancies are crucially important. Therefore, in screening programs, clinical research, and populationbased epidemiological studies, where participants often lack diabetes symptoms or complications, an OGTT is commonly used to detect diabetes, thus adding to the diabetic "pool" an equal-sized group of subjects with unrecognized diabetes and it is misleading trying to assess glucose homeostasis without information on post-prandial glucose metabolism.

normal to slightly reduced hepatic insulin sensitivity and moderate to severe muscle insulin resistance [46]. Individuals with isolated IFG have reduction in both firstphase (0–10 min) during IVGT and early phase (first 30 min) during OGTT insulin secretion but maintained the late-phase (60–120 min) response during OGTT, while Isolated IGT apart from having defect in early-phase insulin secretion in response to OGTT also has a severe deficit in late-phase insulin secretion [47]. The prevalences of IFG and IGT varies widely, varied considerably among different ethnic groups [48]**,** differ significantly in their age and sex distribution; and increase with advancing age. IGT is more frequent in women than in men [49]. A study of 1,245 Italian telephone company employees followed for 11.5 years found that, unlike baseline IGT, baseline IFG did not predict progression to DM, and the categories only overlapped 40% of the time [48]. The natural history of both IFG and IGT is variable, with approx 25% progressing to diabetes, 50% remaining in their abnormal glycaemic state, and 25% reverting to NGT over an observational

American Diabetes Associated did not recommend OGTT to be used commonly

The fasting blood glucose testing in nondiabetic persons poorly identify early signs of dysglycaemia because high postprandial glucose marks the journey of first signs of abnormal glucose regulation and this best predict cardiovascular outcome. Fasting is not really the central issue and it seems to be overemphasized in diagnos-

One problem well known in the measurement of FPG in population studies is the difficulty in ensuring that all the participants have complied with the instructions about fasting [53]. Consequently, some participants with completely normal glucose homeostasis might have been misclassified into impaired fasting glucose category or, more rarely, even into a diabetes category. More so, FPG represents glucose handling during the moment of fasting period only (particularly so, of that moment of blood sampling), and this is affected easily by short-term lifestyle changes such as over activity, stress and drug ingestions. Therefore under these conditions subjects may be classified wrongly if only FPG is used. Knowledge of intraindividual variability of FPG concentrations is essential for meaningful interpretation of patient values. A study of healthy individuals [mean glucose, 4.9 mmol/L (88 mg/ dL)] exhibited within- and between-subject CVs of 4.8–6.1% and 7.5–7.8%, respectively [34]**.** Recent evidence revealed a diurnal variation in FPG, with mean FPG higher in the morning than in the afternoon, indicating that many cases of undiagnosed diabetes would have been missed in patients seen in the afternoon [54]**.** A study with repeated OGTT in 31 nondiabetic adults at 48-hr intervals, demonstrated FPG varied by 10% in 22 participants (77%) and by 20% in 30 participants (97%) [44]**.** Similarly, in population studies of subjects with newly diagnosed diabetes showed a wide distribution of FPG, ranging in one study from <5.0 mmol/1 to >30.0 mmol/L [55]. As a consequence, the sensitivity of the OGTT

in the diagnosis of type 1 and 2 diabetes because it was thought that if FPG is appropriately use it will identify almost the same number of dysglycaemia in the population as the OGTT, and that OGTT is not practicable in routine practice and in many studies OGTT is found to be poorly reproducible, with an estimated rate of

period of 3-5 years [50, 51].

only about 50–66% [52].

ing dysglycaemia.

**120**

**4.5 Advantages of using FPG in screening for dysglycaemia**

*Type 2 Diabetes - From Pathophysiology to Cyber Systems*

**4.6 Disadvantages of FPG in screening for dysglycaemia**

is naturally higher, given the current criteria.

In conclusion, although in clinical practice the OGTT is often regarded as a cumbersome, time-consuming, and patient-unfriendly procedure, for a more detailed and sensitive assessment of the glucose dysmetabolism, the oral glucose tolerance test (OGTT) is the best.

reproducibility of the test (CV = 50%) for 2 h blood glucose. Some of these cause of variations can be minimized with adequate attention to physical activities, dietary preparation and taking care of sample collection at the 2-hr sample (sampling must be done within 5 minutes of 120 minute [66]. The WHO (1999) placed emphasis on the OGTT as the "gold standard", with both fasting and 120-min values being taken into consideration [67]**.** This is by no means a mistake. Only when an OGTT cannot be performed should the diagnosis rely on fasting levels. Other hormones and metabolites can be measured during OGTT, not just glucose and insulin, eg., the

OGTT is the only means of identifying people with IGT, and IGT is an essential diagnostic step, especially when FPG is within the normal range, as these subjects are at high risk not only for type 2 diabetes, but in particular for cardiovascular disease. The main clinical significance of IGT are [68]: (1) It is a risk factor for type

10 years; (2) It predisposes individual to cardiovascular disease (CVD); and (3) It is a component of the metabolic syndrome and its consequences. IGT when identified and subsequently managed will prevent or delayed progression to type 2 diabetes mellitus. It has been indicated by recent studies [69–71] that persons classified with IGT using WHO criteria have increased risk of cardiovascular disease, however many of these subjects do not have impaired fasting glucose (IFG) by the new ADA criteria. Furthermore, the OGTT by WHO criteria identifies diabetes in 2% more individuals than does FPG using ADA criteria [70], although diabetic individuals who are identified by both abnormal FPG and 2-h OGTT have a higher risk of premature death than those with only an increased FPG concentration [71]. More so, fasting plasma glucose alone fails to diagnose in about 30% of cases of diabetes diagnosed by OGTT. OGTT establishes whether an IFG subjects has normal 2hPG and only the simultaneous information obtained from 2hPG (OGTT) allows the screening to become effective. An important matter here is that people with IGT who cannot be identified by either FPG or A1c have ≈40% increased mortality compared with normoglycaemic subjects and lifestyle intervention in these individuals can prevents progression to type 2 diabetes and may reduce their mortality risk to the level observed among normoglycaemic population. These prevention benefits do not exist for A1c or FPG, and this evidences should not be forgotten when deciding the approaches to identify intermediate dysglycaemia. We should therefore make OGTT a priority in an attempt to diagnose hyperglycaemia as early

Thus, using solely FPG, would deceitfully reassure a large proportion of individuals as having NGT, without warning them on the benefits of preventive treatment. Epidemiological studies showed that A1c and plasma glucose (FPG and/or 2-hr OGTT) identify partially different groups of diabetic subjects. While A1c ≥6.5% identifies only ≈30–40% newly diagnosed patients with diabetes [72], a larger percentage was detected by FPG (≈50%), and more so by 2-hr PG(≈90%). These findings are based on several recent studies, including the 2003–2006 NHANES study demonstrating only 30% of diabetic individuals were detected by A1c ≥6.5%, 46% by PFG ≥126 mg/dl, and the IRAS demonstrated 32%, 45%, and 87%, respectively) [73] indicating OGTT is superior. However, the pivotal issue on OGTT is its low reproducibility which is significantly represented by physiologic contexts of the test. The plasma glucose during OGTT are influenced by both insulin sensitivity and secretion, however, impact of other factors particularly incretins, neural responses to nutrient ingestion, gastrointestinal motility and gastric emptying are also important. These factors differ significantly between individuals and are part of non-modifiable factors that govern post-load glucose metabolism and plasma glucose concentration, and are difficult to measure in every

OGTT is the primary test used for the diagnosis of GH hypersecretion.

*Oral Glucose Tolerance Test (OGTT): Undeniably the First Choice Investigation…*

*DOI: http://dx.doi.org/10.5772/intechopen.96549*

2 diabetes, about 20–50% of subjects with IGT develop type 2 diabetes over

as possible.

**123**
